Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats
Abstract
The effect of estrogen (E) on the hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley rats. Animals were bilaterally ovariectomized (OVX), and a Silastic capsule (0.5 cm) containing 17 beta-estradiol was sc implanted. Control animals received a blank capsule. Animals were killed 21 days later. In E-treated rats, we found significantly higher corticosterone (CORT) peak levels 20 min after a 5-sec footshock (1.0 mamp) or exposure to ether vapors (P less than 0.05) compared to those in OVX controls. In addition, the recovery of the ACTH and CORT responses to footshock stress was significantly prolonged (P less than 0.05) in the presence of E. Furthermore, the ACTH and CORT secretory responses to ether stress could be suppressed by exogenous RU 28362 (a specific glucocorticoid receptor agonist; 40 micrograms/100 g BW for 4 days) in OVX controls (P less than 0.05), but not in E-treated animals. These data suggest that E can impair glucocorticoid receptor-mediated delayed or slow negative feedback. Consequently, we examined the influence of E on mineralocorticoid and glucocorticoid receptor concentrations using in vitro binding assays. E did not alter mineralocorticoid or glucocorticoid receptor concentrations in any of the brain regions examined. The administration of RU 28362 (40 micrograms/100 g BW for 4 days) to OVX control or E-treated rats significantly down-regulated hippocampal glucocorticoid receptor (P less than 0.02) in control rats only. In contrast, aldosterone administration (40 micrograms/100 g BW for 4 days) significantly down-regulated hippocampal glucocorticoid receptor (P less than 0.0008) in both control and E-treated animals. Thus, E treatment results in a loss of the glucocorticoid receptor's ability to autoregulate; this suggests that E may cause a functional impairment of the glucocorticoid receptor even though receptor binding appears normal. These findings suggest that hyperactivation of the hypothalamic-pituitary-adrenal axis after stress in E-treated rats is due in part to impaired glucocorticoid receptor-mediated slow negative feedback.
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Estradiol both enhances and inhibits HPA function in laboratory observations.
“These opposing actions of estradiol—with ER-α amplifying, and ER-β reducing HPA function—are in agreement with laboratory observations that estradiol both enhances (72, 73) and inhibits (74, 75) HPA function.”
From Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis (2020) · cites this paper as [73]
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- Authors
- Burgess, L. H., & Handa, R. J.
- Affiliations
- Loyola University Chicago (US)
- ORCID
- Handa, R J
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1992-09
- Volume
- 131
- Issue
- 3
- Pages
- 1261-1269
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2092107317
- Cited by
- 445
- References
- 36
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 11 · 2020: 8 · 2019: 14 · 2018: 10 · 2017: 8 · 2016: 13 · 2015: 13 · 2014: 19 · 2013: 20 · 2012: 10
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- estrogen, hypothalamic-pituitary-adrenal axis, ACTH secretion, corticosterone, glucocorticoid receptor, negative feedback, RU 28362, aldosterone, hippocampus, ovariectomy, stress response, mineralocorticoid receptor, female rats, receptor autoregulation
- MeSH terms
- Adrenocorticotropic Hormone, Androstanols, Animals, Brain, Corticosterone, Cytosol, Dexamethasone, Drug Implants, Electroshock, Estradiol, Female, Hippocampus, Organ Specificity, Ovariectomy, Rats, Inbred Strains, Receptors, Glucocorticoid, Receptors, Steroid, Silicone Elastomers, Stress, Psychological, Time Factors, Rats
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